Molecular genetics and dysmorphology Flashcards
Human genome sequence classes
Single copy sequences (non-repetitive) - genes
Repetitive - interspersed repeats (Alu repeats); satellite DNA (large blocks of repetitive sequence, heterochromatin)
How do genes evolve?
Duplication and divergence
What are processed genes?
Intronless copies of other genes - usually from remote parent genes.
Reverse transcription and reintegration usually causes e.g. retroviruses
Most are non-functional
Classifications of repetitive DNA
Satellite DNA are large blocks of repeat DNA sequences
Interspersed repeats are scattered around the genome
Satellite DNA
Large blocks at centromeres and heterochromatic chromosomal regions. Simple tandemly repeated sequences.
Many types e.g. Alphoid DNA centromere repeat, chromosome specific
Alphoid DNA
Type of satellite DNA found at centromeres
171-bp repeat unit
Repeat unit sequences shows chromosome specific sequence variation.
Alphoid DNA is required for assembly of the centromere.
Remember can be chromosome specific.
Interspersed repeats
Scattered around the genome. Individual copies are present at many locations either between or within genes.
Alu repeat: 500k repeats, 300bp, 5% of genome
Dispersed by retrotransposition. Role in generation of molecular pathology.
What can go wrong?
Problems with alignment/recognition
Interspersed repeats which unequally crossover
Mutations: deletions/insertions; gross rearrangements; point mutations; trinucleotide repeat expansions
Example of large deletions
DMD
Example of large duplication
Charcot-Marie-Tooth Disease
Example of gross rearrangement
Haemophilia A
Haemophilia A mutation description
Turns back on itself and the inverted segment then binds in place
Common silent point mutation name
Polymorphism
Point mutation changing aa name
Missense
Hypermutability of CpG dinucleotides mechanisms
Methylation
Deamination
Mismatch repair
What is one-third of mutations
CG->TG
Point mutation changing aa to a non-existent sequences name
Nonsense
Makes truncated protein which can be exploited for mutation detection
Frameshift mutation
Alter protein sequence beyond mutation which may truncate protein
Reference sequence for: genomic DNA
g.
Reference sequence for: cDNA
c.
Reference sequence for: Protein
p.
Trinucleotide repeat expansions
Polyglutamine repeats (CAG)
Large non-coding repeat expansions
Mutational instability
Polyglutamine repeats (CAG)
Huntington’s disease
Spinocerebellar ataxias
Large non-coding repeat expansions
Fragile X syndrome (CGG repeat expansion)
Myotonic dystrophy
Mutational instability
Occasional e.g. Huntington’s
Frequent e.g. Fragile X
Morphology definition
The scientific study of the structure and form of either animals and plants or words and phrases - mainly face
Congenital malformations prevalence
2-3% of births
22q11.2 deletion - prevalence, affects, signs & symptoms
Very variable 1in5k Learning difficulties in 70% Congenital heart defect in 75% Cleft palate 15% Velopharyngeal insufficiency 32%
Achondroplasia - prevalence, affects, signs & symptoms
1in20k Autosomal dominant Risk increases with paternal age Rhizomelic limb shortening Short stature Foreamen magnum compression/hydrocephalus
Beckwith-Wiedemann Syndrome - prevalence, affects, signs & symptoms
1in10k Large tongue Eat pits/creases Exomphalos Hemihypertrophy Neonatal hypoglycaemia Increased risk of Wilms tumour (nephroblastoma)
Down Syndrome - prevalence, affects, signs & symptoms
Commonest chromosomal disorder 1in800 live births Learning difficulties Congenital heart defects Hypotonia in neonates SIngle palmar crease Cataracts Hearing impairment Hypothyroidism Leukaemia Atlanto-axial instability Alzheimer's disease
Single palmar crease is associated with?
Down syndrome
Kabuki syndrome - prevalence, affects, signs & symptoms
1 in 30k
Learning difficulties
Congenital heart disease (50%)
Poor growth
Hearing impairment
Cleft palate
Premature breast development
Persistent fetal finger pads (96%)
What is a persistent foetal finger pad?
Prominent ventral soft tissue on finger tips or toes
What is Mosaicism?
Hypo / hyper pigmented patches
May follow Blaschko’s lines
Diagnosis via skin biopsy
Peutz-Jeghers syndrome - prevalence, affects, signs & symptoms
1 in 50k
GI polyps - bleeding&obstruction
Malignancies: colorectal, gastric, pancreatic, breast, ovarian
Treacher-Collins Syndrome - prevalence, affects, signs & symptoms
1 in 50k
Autosomal dominant
Variable presentation
Cleft palate
Hearing impairment
Waardenburg syndrome - prevalence, affects, signs & symptoms
1 in 250k
Sensorineural hearing impairment Iris heterochromia Premature greying White forelock Skin hypopigmentation Congenital malformations (Hirschsprungs/VSD)
William’s Syndrome - chromosome change, prevalence, affects, signs & symptoms
7q11 deletion
1 in 20k
Learning difficulties
‘Cocktail party speech’
Congenital heart disease - (supravalvular aortic stenosis, peripheral pulm. artery stenosis)
Hypercalcaemia
